{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:05:27Z","timestamp":1791515127376,"version":"4.3.4"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with <jats:italic>ALK<\/jats:italic>\u2009+\u2009metastatic non-small cell lung cancer (NSCLC). The study investigated the drug\u2013drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with <jats:italic>ALK<\/jats:italic>\u2009+\u2009NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750\u00a0mg once daily.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with <jats:italic>ALK<\/jats:italic>\u2009+\u2009NSCLC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-020-04180-3","type":"journal-article","created":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T11:04:23Z","timestamp":1609758263000},"page":"475-486","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug\u2013drug interaction study in patients with ALK\u2009+\u2009advanced tumors"],"prefix":"10.1007","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5254-972X","authenticated-orcid":false,"given":"Felipe K.","family":"Hurtado","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"de Braud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"De Castro Carpe\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jose","family":"de Miguel Luken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne Y.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"McCulloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2235-1250","authenticated-orcid":false,"given":"Morten","family":"Mau-Sorensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,4]]},"reference":[{"issue":"1","key":"4180_CR1","doi-asserted-by":"publisher","first-page":"R11","DOI":"10.1530\/Jme-11-0004","volume":"47","author":"A Barreca","year":"2011","unstructured":"Barreca A, Lasorsa E, Riera L, Machiorlatti R, Piva R, Ponzoni M, Kwee I, Bertoni F, Pp P, Sa P, Inghirami G (2011) Anaplastic lymphoma kinase in human cancer. 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Y.Y.L. was a Novartis employee until study completion. F.d.B. reports personal fees from Roche, outside the submitted work. F.J.C.C. reports personal fees (advisory board) from Pfizer, from Hoffmann-La Roche, Takeda, Novartis, during the conduct of the study; personal fees (advisory board) from Bristol-Myers Squibb, Merck-Sharp & Dohme, outside the submitted work. Remaining authors have nothing to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was designed and conducted in accordance with the ethical principles of the Declaration of Helsinki and the guidelines for Good Clinical Practice, with applicable local regulations. The study protocol and all amendments were reviewed by an independent ethics committee or institutional review board for each center.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All patients provided written informed consent before screening.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}